Lithium is the treatment of choice for manic-depressive bipolar illness and is also used for its prophylactic effect in unipolar depression and a number of other disorders. We have been studying the effects of lithium on cholinergic processes in rat brain and in blood from patients with psychiatric disorders. These studies will be continued and expanded as follows. This project is designed to study the interactions between lithium and cyclic nucleotides, calcium, phosphoinositide turnover and cholinergic activity in rat brain and the effects of lithium on blood cholinergic processes in psychiatric patients with the major goal of identifying the therapeutic mechanisms of action of lithium. Reduced cholinergic activity may play a role in mania and lithium stimulates cholinergic activity. Lithium appears to have significant effects both presynaptically and postsynaptically. The presynaptic action of lithium results in enhanced release of acetylcholine. Hypotheses will be tested to identify the mechanisms of action of lithium with a focus on cyclic nucleotides, calcium and phosphoinositide hydrolysis. The effects of lithium on in vivo levels of cAMP and cGMP (basal and agonist stimulated) and on in vitro effects of cAMP will be measured. Calcium influx and efflux in synaptosomes and ATPase activities will be measured in the presence and absence of lithium and in control and lithium treated rats. The effects of in vitro and in vivo lithium on modulation of acetylcholine release from brain slices will be measured. Agonist-stimulated and basal phosphoinositide metabolism will be measured in the presence and absence of lithium and following chronic lithium treatment in brain slices, in a newly characterized brain membrane preparation and in vivo. Finally, lithium potentiates the effects of pilocarpine in vivo resulting in status epilepticus. Other convulsants will be tested to identify how widespread is this effect of lithium and purinergic and GABAergic drugs will be used to identify the mechanism of this effect. Patients treated with lithium have RBC choline levels five to ninety-fold higher than controls and reduced RBC choline transport. These effects of lithium will be studied with regard to RBC/plasma lithium, demographic data and clinical data to identify disease or response specific correlations.